The Pima Indians have the highest reported prevalence and incidence of noninsulin dependent diabetes mellitus (NIDDM) of any population in the world. The diabetes occurs more frequently in offspring of a diabetic mother than in offspring of nondiabetic parents. The reasons for this are unknown. In this study we have planned to determine the metabolic abnormality that predisposes the former group of offspring to develop NIDDM. Due to the extremely high incident rate of NIDDM in this population a sufficient number of offspring of diabetic mothers will develop NIDDM within five years such that it will be possible to determine which metabolic parameter, if any, is predictive of NIDDM in this population. We will be studying many aspects of carbohydrate metabolism, both in vivo and in vitro, in an initial cross-sectional comparison and a longitudinal study. To date, approximately 200 subjects have been enrolled in the initial cross-sectional phase of this project. Approximately 60 subjects have returned for their first yearly follow-up studies. Considerable data has already been collected. Increasing obesity is only weakly associated with evidence of a "post-receptor defect" in insulin action in vivo and in vitro in isolated abdominal adipocytes. Surprisingly there are only very weak correlations between maximal insulin stimulated glucose transport in isolated adipocytes and the maximal insulin stimulated glucose disposal rate in vivo. The maximal oxygen uptake appears to account for about 25% of the observed variance of insulin action at lower high insulin concentrations. At lower insulin concentrations, obesity appeared to be more correlated with insulin action in vivo but again could only account for a very small amount of the variance observed in in vivo insulin action. Mildly glucose intolerant subjects compared to normal glucose tolerant subjects appear to have a increased ED 50 for insulin stimulated glucose transport in isolated adipocytes.